tbuckley/cabot-search huggingface dataset:
Abstract 2382: Aberrant glycogen accumulation alters gene expression and promotes lung tumor progression <i>in vivo</i>
Authors: Jessica Faith Lamb, Lindsey R. Conroy, Alexis N. James, Michael D. Buoncristiani, Eric R. Relich, Lindsay E. Young, Christine F. Branson, Ramon C. Sun
Journal: Cancer Research (2022)

Abstract Lung cancer is one of the most prevalent cancers worldwide, accounting for nearly two million new cases each year. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is the leading cause of cancer related mortalities worldwide. LUAD has an extremely poor five-year survival rate, which is likely due to cases being diagnosed at advanced stages and thus being more difficult to treat the metastatic disease. Identifying the molecular processes that contribute to disease progression is a critical goal in lung cancer research that could lead to predictive biomarkers and novel therapies. Glycogen is the primary form of carbohydrate storage in mammalian cells, and its degradation product, Glucose 6-Phosphate (G6P) feeds directly into glycolysis, making glycogen intimately connected to central carbon metabolism. Recently, aberrant glycogen accumulation in lung tumors has been reported to promote lung cancer progression, driven by largely unknown mechanisms. We recently generated a transgenic KRASG12D/p53-/- LUAD mouse model that also lacks the glycogen phosphatase laforin (LKO). This model develops increased glycogen accumulation in the lungs and displays accelerated tumor growth compared to the KRASG12D/p53-/- control (WT), as measured by Ki67 staining. To identify potential biological processes perturbed by LUAD-glycogen, we performed RNA-seq on lung tumors resected from WT and LKO mice. We identified over 300 genes that are differentially expressed between WT and LKO lung tumors. Specifically, gene set enrichment analysis (GSEA) revealed genes that were upregulated in LKO lung tumors were involved in extracellular matrix remodeling, cell-to-cell communication, and cell proliferation. All of these processes are implicated in tumor growth, which supports our initial observation that LKO mice have increased tumor burden and disease progression. Our findings ultimately highlight several potential mechanisms by which LUAD-glycogen promotes LUAD tumor progression, which can be further investigated to identify novel biomarkers and therapeutic targets. Citation Format: Jessica Faith Lamb, Lindsey R. Conroy, Alexis N. James, Michael D. Buoncristiani, Eric R. Relich, Lindsay E. Young, Christine F. Branson, Ramon C. Sun. Aberrant glycogen accumulation alters gene expression and promotes lung tumor progression in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2382.
Abstract 5641: Tumor cell intrinsic factors in colorectal cancer immune evasion
Authors: Dechen Wangmo, Xianda Zhao, Angelo Yuan, Travis Gates, Subree Subramanian
Journal: Cancer Research (2022)

Abstract The poor response of most colorectal cancer (CRC) patients to immunotherapy is a major unmet clinical need. Although early detection through screening has reduced CRC incidence, the prognosis for metastatic CRC is poor. In the past decade, immune checkpoint inhibitors (ICIs) have been a major clinical breakthrough with promising clinical benefits in many cancer types, but its efficacy is limited in most (~85%) CRC patients. ICIs preferentially have robust responses from tumors with pre-existing T cell infiltration. However, most CRC lacks robust T-cell infiltration due to immune evasion mechanisms. Therefore, it is crucial to characterize factors shaping immune evasion to improve the response to ICIs. We hypothesize that targeting tumor-cell intrinsic factors can overcome T cell exclusion and will sensitize the tumor to ICIs. To elucidate the factors underlying ICI resistance, it is critical that preclinical models faithfully recapitulate the tumor physiology and genetics of the human disease. Therefore, we developed a tumor organoid (tumoroids) model system adapted from Jacks lab that harbors shApc, KrasG12D, p53-/- and Smad4-/- (shAKPS) mutations, which are co-mutated with high frequency and associated with poor prognosis. We demonstrated that tumoroids with only shApc and KrasG12D mutations can form a solid tumor in two weeks. Addition of p53-/- and Smad4-/- mutations drives invasiveness and metastasis. The shAKPS tumoroids present key features of advanced CRC that are unresponsive to ICIs including invasive tumor, metastasis, and T cell exclusion. Using CRISPR/Cas9 screening and integrative immune score analysis, we identified potential immune evasive genes. To define their expression profile in the tumor, we performed TCGA data analysis in fourteen different cancer types. Furthermore, we performed correlation tests to determine their role in immune cell infiltration and T cell dysfunction. Our results show that these immune suppressive genes are overexpressed in tumor tissues, and negatively correlate with CD8+ T cell infiltration. Our findings suggest that overexpression of immune suppressive genes in cancer cells may cause T cell dysfunction and exclusion in tumors. Furthermore, the functional role of these immune suppressive genes will be characterized using shAKPS mutant organoids and in vivo orthotopic CRC tumor models. Citation Format: Dechen Wangmo, Xianda Zhao, Angelo Yuan, Travis Gates, Subree Subramanian. Tumor cell intrinsic factors in colorectal cancer immune evasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5641.
Abstract 3572: Oncolytic virotherapy with the HSV-1 (VC2) vaccine strain induces anti-tumor T-cell responses in the murine 4T1 breast cancer model
Authors: Rafiq Nabi, Farhana Musarrat, Vladimir Chouljenko, Konstantin Kousoulas
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) plays important roles in suppression of anti-tumor immune responses. Immune suppression is achieved by multiple mechanisms including interfering with antigen presentation and inhibition of effector T-cell tissue infiltration. Altering specific TME properties can reduce immune-suppression and improve anti-tumor immunity with abscopal effects. Oncolytic Virotherapy (OV) is a promising approach for cancer treatment. We evaluated the efficacy of the HSV-1 (VC2) vaccine strain for the treatment of breast cancer using the murine stage-4 (4T1) syngeneic and immunocompetent breast cancer mouse model. Following Intratumoral (IT) injection of VC2 in mice bearing implanted 4T1 tumors, treatment efficacy was evaluated by monitoring tumor weight, immune infiltration, and metastasis in the lung. Animals treated with VC2 via the IT route exhibited significantly reduced metastasis and improved intra-tumoral T-cell infiltration. Improved T-cell infiltration was not due to viral replication since improved parameters were observed during late times post VC2 treatment when no viral replication was detectable. The total area of metastasis in the lung was significantly reduced compared to control groups. VC2 treated animals via the IT route had significantly higher cytotoxic splenocytes, evident by the in-vitro killing of 4T1 cells, compared to the control group. This improved cytotoxic activity, intratumoral T-cell infiltration, and reduced metastasis in the lung suggest that IT administration of VC2 altered TME in a way that induced better antigen recognition, processing, and presentation resulting in improved anti-tumor immune responses with an abscopal effect in the lung. Further understanding of the mechanisms involved in the observed improved anti-tumor immune responses will help improve treatment efficacy and provide new approaches for the treatment of solid tumors. Citation Format: Rafiq Nabi, Farhana Musarrat, Vladimir Chouljenko, Konstantin Kousoulas. Oncolytic virotherapy with the HSV-1 (VC2) vaccine strain induces anti-tumor T-cell responses in the murine 4T1 breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3572.
Abstract 55: A genome-wide atlas of recurrent repeat expansions in human cancer genomes
Authors: Graham S. Erwin, Gamze Gursoy, Rashid Al-Abri, Christian Hoerner, Egor Dolzhenko, Michael Eberle, Alice Fan, John Leppert, Mark Gerstein, Michael P. Snyder
Journal: Cancer Research (2022)

Abstract Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 40 neurodegenerative diseases. However, repeat expansions have not been systematically examined in contexts beyond neurological disorders. In a specific form of cancer, termed microsatellite instability (MSI), mutations accumulate in short (&amp;lt;50 bp) tracts of TRs, suggesting that cancer genomes may also harbor larger repeat expansions. Here, we developed a new method to systematically identify TR alterations and applied it to the analysis of 2,622 cancer genomes spanning 29 cancer types. We identified 160 recurrent repeat expansions (rREs) in 7 cancers; most (155/160) rREs were cancer-subtype specific. Surprisingly, rREs were not correlated with MSI status, demonstrating that they arise by a distinct process. We also found that rREs are situated closer to candidate cis-regulatory elements than expected by chance, suggesting a role in gene regulation. Interestingly, an rRE in the intron of UGT2B7, detected in 34% of renal cell carcinoma samples, is associated with a decrease in gene expression. Our results demonstrate that rREs are an important and unexplored source of genetic variation in human cancer and provide a large catalog for further study. Citation Format: Graham S. Erwin, Gamze Gursoy, Rashid Al-Abri, Christian Hoerner, Egor Dolzhenko, Michael Eberle, Alice Fan, John Leppert, Mark Gerstein, Michael P. Snyder. A genome-wide atlas of recurrent repeat expansions in human cancer genomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 55.
Abstract 5781: Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients
Authors: Li Li, Kewen He, Jiaohui Pang, Yang Xu, Yang Shao, Shuanghu Yuan, Jinming Yu
Journal: Cancer Research (2022)

Abstract Background: The high recurrence rate of stage pIIIA-N2 NSCLC patients may reflect inadequate removal of all residual tumor cells despite conventional histologic negative surgery margin. The NGS-detected BRM status was possible to serve as a more accurate examination to identify those patients with a high-risk of postoperative recurrence. Methods: We retrospectively studied 119 stage IIIA-N2 NSCLC patients who received curative-intent surgery plus adjuvant chemotherapy/chemoradiotherapy, and all of the patients were classified with negative resection margin by the conventional histologic method. Each patient had paired tumor and bronchial resection margin (BRM) samples, which were analyzed using next-generation sequencing (NGS) of 474 cancer-related genes, and we explored the prognostic values of various clinical and molecular features. Results: Among the 119 stage IIIA-N2 NSCLC patients with histologic negative resection margins, the BRM samples from 56 patients (47.1%) were positive for tumor mutations, including multiple lung cancer driver mutations. The number and the variant allele frequency of genetic alterations in BRM samples were generally lower than that of the paired tumor samples. Notably, patients who were positive for NGS-detected BRM mutations had significantly shorter disease-free survival (DFS) than the negative patients (p=0.001, HR 2.18, 95%CI 1.37~3.47). Several other clinical/molecular features were also found to be significantly associated with DFS, including the metastatic lymph node ratio (MLNR), smoking history, and KRAS mutation status, and NGS-assessed BRM status remained to be statistically significant in multivariable analysis by including all of these prognostic factors (p =0.020, HR 1.82, 95%CI 1.10~3.02). Conclusions: We demonstrated that the molecular positive margin of surgical resections was a strong and independent biomarker for disease recurrence in pIIIA-N2 NSCLC patients. Our results emphasized the clinical utility of molecular diagnostic approaches to detect minimal residual disease after surgical resection, which could potentially facilitate the stratification of high-risk patients for personalized and appropriate treatments. Citation Format: Li Li, Kewen He, Jiaohui Pang, Yang Xu, Yang Shao, Shuanghu Yuan, Jinming Yu. Molecular positive margin of surgical resections is a strong biomarker for tumor recurrence in pIIIA-N2 NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5781.
Abstract 4238: A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells
Authors: Tanmoy Saha, Ruparoshni Jaybalan, HaeLin Jang, Shiladitya Sengupta
Journal: Cancer Research (2022)

Abstract Trafficking of mitochondria from immune cells to cancer cells via physical nanotubes is a new mechanism by which cancer cells undergo immune evasion. This results in depletion of T cell, which can limit the efficacy of classical immune checkpoint inhibitors. Here we introduce a novel pharmacological inhibitor that inhibits nanotube-mediated mitochondria transfer from immune cell to cancer cell. Our preliminary study implicates the exocyst complex in the nanotube assembly. We performed molecular dynamic simulations to identify the potential inhibitors for the exocyst proteins. We have identified a drug candidate, TS-1, which successfully inhibits the mitochondria transfer from immune cell to cancer cell. Currently we are exploring the modification of the structural component to increase the inhibitory potential of the drug. TS-1-loaded liposome significantly inhibited tumor growth in a 4T1 metastatic breast cancer mouse model. We observed considerable increase in intratumoral T cell population with treatment. Furthermore, the use of TS-1 in combination with an anti-PD1 inhibitor resulted in effective tumor reduction in the 4T1 model, which typically responds poorly to anti-PD1 therapy alone. Conclusion: Taken together, the inhibition of nanotube-mediated mitochondrial hijacking from immune cells emerges as an approach for the development of next generation of immunotherapy agents. Citation Format: Tanmoy Saha, Ruparoshni Jaybalan, HaeLin Jang, Shiladitya Sengupta. A novel immunotherapy approach by inhibiting nanotube-mediated mitochondrial trafficking between cancer cells and T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4238.
Abstract 1760: The antibody-drug conjugate GENA-111 conjugated to auristatin F shows therapeutic potency in BCAM positive epithelial cancer
Authors: Hyunkyung Yu, Nathalie Bellocq, Youngeun Ha, Hyunuk Kim, Yunyeon Kim, Bu-Nam Jeon, Léo Marx, Mathilde Pantin, Hyunjin Yoo, Seungmin Byun, Joo-Yeon Chung, Mi Young Cha, Patrick Garrouste, Frédéric Lévy
Journal: Cancer Research (2022)

Abstract Antibody-drug conjugates (ADCs) are considered as promising cancer treatment modalities that combine the selectivity of antibodies and the cytotoxic properties of payloads using chemical linkers. However, despite their success, ADCs still suffer from drawbacks, e.g., systemic toxicity, which limit their potential clinical applications. The systemic toxicity of an ADC is mainly related to the stability of its linker, and to the selectivity of its antibody towards the targeted antigen expressed on cancer cells. Lu/BCAM (Lutheran/basal cell adhesion molecule) is a member of the immunoglobulin superfamily and is a receptor for laminin, a protein that facilitates cell adhesion, migration, and invasion. A growing number of studies show that BCAM plays an essential role in tumor progression and is overexpressed on epithelial cancers e.g., skin cancer. Here we describe GENA-111, a human monoclonal anti-BCAM IgG4 (S228P) antibody that binds to human BCAM with high affinity, and that is significantly internalized by BCAM-positive tumor cells. We also describe the GENA-111-auristatin F ADC, wherein the GENA-111 antibody has been armed with an auristatin F derivative using a new linker technology and a stabilized thiol maleimide conjugation. This new linker technology comprises a cleavable peptidic sequence that facilitates multidrug attachment and the production of ADCs with tailored drug-to-antibody ratios (DARs). Cytotoxic drugs are rapidly and selectively released from the linker by the carboxypeptidase activity of Cathepsin B. In vitro cytotoxicity examination showed the potent cytotoxic effects of this GENA-111-auristatin F ADC on BCAM-expressing tumor cells, with a positive correlation between cytotoxicity and BCAM expression. Moreover, this ADC was also shown to significantly reduce the growth of tumor cells, including A431, T47D, and Huh7. The GENA-111-auristatin F ADC was evaluated in a xenograft mouse model established by subcutaneous injection of A431 cells, a BCAM positive human skin cancer cell line. The results of this study will be presented and discussed. Taken together, our data suggest that an ADC targeting BCAM e.g., GENA-111-auristatin F, might be a promising treatment strategy for BCAM positive epithelial cancer patients. Citation Format: Hyunkyung Yu, Nathalie Bellocq, Youngeun Ha, Hyunuk Kim, Yunyeon Kim, Bu-Nam Jeon, Léo Marx, Mathilde Pantin, Hyunjin Yoo, Seungmin Byun, Joo-Yeon Chung, Mi Young Cha, Patrick Garrouste, Frédéric Lévy. The antibody-drug conjugate GENA-111 conjugated to auristatin F shows therapeutic potency in BCAM positive epithelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1760.
Abstract 3773: Mitochondrial fusion is required to support higher rates of respiration in proliferating cancer cells
Authors: Yahui Wang, Conghui Yao, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P. Shriver, Jason Weber, Gary J. Patti
Journal: Cancer Research (2022)

Abstract Proliferating cancer cells exhibit an elevated rate of glucose consumption and lactate excretion, a phenomenon described as the “Warburg effect”. Although increased glycolytic flux in proliferating cells is well established, metabolic changes associated with mitochondria still remain elusive. Here, using various inducible quiescence models and mass spectrometry-based metabolomics, we directly compared mitochondrial respiration and TCA cycle activity from the same cells in the proliferative and quiescent states. We found that mitochondrial respiration and TCA cycle flux is significantly increased during proliferation in both transformed and non-transformed cell lines. This increase was supported by mitochondrial fusion rather than mitochondrial biogenesis. Notably, as cells transitioned from a quiescent state to a proliferative state, the elongation of mitochondria occurred as quickly as 3 hours. Our results reveal that the Warburg effect, which was originally associated with dysfunctional mitochondria, does not necessitate decreased mitochondrial respiration. Rather, in many proliferating cancer cells, mitochondrial respiration is actually elevated, underscoring the importance of mitochondrial respiration during proliferation. Citation Format: Yahui Wang, Conghui Yao, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P. Shriver, Jason Weber, Gary J. Patti. Mitochondrial fusion is required to support higher rates of respiration in proliferating cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3773.
Abstract 479: The role of diffusion in molecular networks: Diffusion coefficients in describing the development of cancer
Authors: Narayana Garimella
Journal: Cancer Research (2022)

Abstract To study and forecast the developments of cancers, the molecular networks, compositional fluctuations, diffusion in networks and altogether the biological processes resulting at cellular and intracellular levels, are highly important. Focusing on diffusion coefficients as the translational biomarkers to quantify the nucleation and growth of tumors and cancers has potential advantages. Because, diffusion coefficients act as guiding tools in preventing or treating the cancers and associated adversities. Collectively the biological, pharmacological and toxicological indicators during and prior to the course of cancer are taken as measures for the data over specific distances of the molecules to determine diffusion coefficients. Because, multiple mechanisms are simultaneously responsible in altering the compositions. In this work, the mass transportation in both healthy individuals and cancer patients are taken into account to compare and contrast the initiation and spread of cancers in the light of immunology and immunotherapy. Measurements through incoherent motion diffusion-weighted imaging (IVIM-DWI) and echo planar magnetic resonance (MR) imaging are applied in determining the diffusion parameters. Diffusion coefficients were within the ranges of 0.1 to 5 X 10-3 mm2/sec. Perfusion played important role in quantifications. Magnitudes of diffusion coefficients are used to forecast biological prevalence and to develop prevention and treatment therapeutics. Citation Format: Narayana Garimella. The role of diffusion in molecular networks: Diffusion coefficients in describing the development of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 479.